The present invention relates to a process for preparing cyclic thioamides useful for preparing aralkyl and aralkylidene heterocyclic lactams and imides, which are selective agonists and antagonists of serotonin 1 (5-HT1) receptors, specifically, of one or both of the 5-HT1A and 5-HT1D receptors, useful in treating or preventing migraine, depression and other disorders for which a 5-HT1 agonist or antagonist is indicated.
European Patent Publication 434,561, published on Jun. 26, 1991, refers to 7-alkyl, alkoxy, and hydroxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes. The compounds are referred to as 5-HT1 agonists and antagonists useful for the treatment of migraine, depression, anxiety, schizophrenia, stress and pain.
European Patent Publication 343,050, published on Nov. 23, 1989, refers to 7-unsubstituted, halogenated, and methoxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes as useful 5-HT1A ligand therapeutics.
PCT publication WO 94/21619, published Sep. 29, 1994, refers to naphthalene derivatives as 5-HT1 agonists and antagonists.
PCT publication WO 96/00720, published Jan. 11, 1996, refers to naphthyl ethers as useful 5-HT1 agonists and antagonists.
European Patent Publication 701,819, published Mar. 20, 1996, refers to the use of 5-HT1 agonists and antagonists in combination with a 5-HT re-uptake inhibitor.
Glennon et al., refers to 7-methoxy-1-(1-piperazinyl)-naphthalene as a useful 5-HT1 ligand in their article xe2x80x9c5-HT1D Serotonin Receptorsxe2x80x9d, Clinical Drug Res. Dev., 22, 25-36 (1991).
Glennon""s article xe2x80x9cSerotonin Receptors: Clinical Implicationsxe2x80x9d, Neuroscience and Behavioral Reviews, 14, 35-47 (1990), refers to the pharmacological effects associated with serotonin receptors including appetite suppression, thermoregulation, cardiovascular/hypotensive effects, sleep, psychosis, anxiety, depression, nausea, emesis, Alzheimer""s disease, Parkinson""s disease and Huntington""s disease.
World Patent Application WO 95/31988, published Nov. 30, 1995, refers to the use of a 5-HTD1D antagonist in combination with a 5-HT1A antagonist to treat CNS disorders such as depression, generalized anxiety, panic disorder, agoraphobia, social phobias, obsessive-compulsive disorder, post-traumatic stress disorder, memory disorders, anorexia nervosa and bulimia nervosa, Parkinson""s disease, tardive dyskinesias, endocrine disorders such as hyperprolactinaemia, vasospasm (particularly in the cerebral vasculature) and hypertension, disorders of the gastrointestinal tract where changes in motility and secretion are involved, as well as sexual dysfunction.
G. Maura et al., J. Neurochem, 66 (1), 203-209 (1996), have stated that administration of agonists selective for 5-HT1A receptors or for both 5-HT1A and 5-HT1D receptors might represent a great improvement in the treatment of human cerebellar ataxias, a multifaceted syndrome for which no established therapy is available.
European Patent Publication 666,261, published Aug. 9, 1995 refers to thiazine and thiomorpholine derivatives which are claimed to be useful for the treatment of cataracts.
The present invention relates to a process for preparing a compound of the formula 
wherein b is 0, 1, 2 or 3; Y is oxygen, sulfur, NH or N-acetyl; and each R3 is independently selected from the group consisting of halo, cyano, (C1-C6)alkyl, (C1-C6)alkoxy and trifluoromethyl; comprising reacting a compound of the formula 
xe2x80x83with a dehydrating agent.
The present invention also relates to a more preferred process for preparing the compound of formula I, wherein the dehydrating agent is acetic anhydride.
The present invention also relates to a process for preparing a compound of the formula 
comprising reacting a compound of the formula 
with haloacetic acid in the presence of a base.
The present invention also relates to a more preferred process for preparing the compound of formula II, wherein the haloacetic acid is bromoacetic acid.
The present invention also relates to a more preferred process for preparing the compound of formula II, wherein the base is potassium hydroxide.
The present invention also relates to a process for preparing a compound of the formula 
comprising reacting a compound of the formula 
with a reducing agent and reacting the compound so formed with hydrochloric acid.
The present invention also relates to a more preferred process for preparing the compound of formula III, wherein the reducing agent is borane tetrahydrofuran complex.
The present invention also relates to a process for preparing a compound of the formula 
comprising reacting a compound of the formula 
with hydroxyacetic acid, mercaptoacetic acid or 2-aminoacetic acid.
The present invention also relates to a more preferred process for preparing the compound of formula IV, wherein the compound of formula V is reacted with mercaptoacetic acid.
The present invention also relates to a process for preparing a compound of the formula 
wherein b is 0, 1, 2 or 3; Y is oxygen, sulfur, NH or N-acetyl; and each R3 is independently selected from the group consisting of halo, cyano, (C1-C6)alkyl, (C1-C6)alkoxy and trifluoromethyl; comprising
(a) reacting a compound of the formula 
xe2x80x83with hydroxyacetic acid, mercaptoacetic acid or 2-aminoacetic acid;
(b) reacting a compound of formula IV so formed 
xe2x80x83with a reducing agent and reacting the intermediate compound so formed with hydrochloric acid;
(c) reacting a compound of formula III so formed 
xe2x80x83with haloacetic acid in the presence of a base; and
(d) reacting a compound of formula II so formed 
xe2x80x83with a dehydrating agent.
The present invention also relates to a more preferred process for preparing the compound of formula I, wherein the compound of formula V is reacted with mercaptoacetic acid; the reducing agent is borane tetrahydrofuran complex; the base is potassium hydroxide; the haloacetic acid is bromoacetic acid; and the dehydrating agent is acetic anhydride.
The present invention also relates to a compound of the formula 
The present invention also relates to a compound of the formula 
The present invention also relates to a compound of the formula 
The following reaction Schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated, b, Y and R3 in the reaction Schemes and the discussion that follow are defined as above. 
In reaction 1 of Scheme 1, the aniline compound of formula V is converted to the corresponding compound of formula IV, wherein Y is oxygen, sulfur, NH or N-acetyl, by reacting V with hydroxyacetic acid, mercaptoacetic acid or 2-aminoacetic acid, in the presence of an aprotic solvent, such as toluene. The reaction mixture so formed is heated to reflux for a time period between 16 hours to about 24 hours, preferably about 20 hours.
In reaction 2 of Scheme 1, the compound of formula IV is converted to the corresponding compound of formula III by reducing IV with a reducing agent, such as borane tetrahydrofuran complex. The compound so formed is then treated with anhydrous hydrochloric acid in the presence of a polar protic solvent, such as ethanol. The reaction is carried out at a temperature between about 10xc2x0 C. to about 20xc2x0 C., preferably about 15xc2x0 C., for a time period between about 2 hours to about 4 hours, preferably about 3 hours.
In reaction 3 of Scheme 1, the compound of formula III is converted to the corresponding compound of formula II by first treating III with a base, such as potassium hydroxide, under inert atmosphere, in the presence of a polar protic solvent, such as ethanol, at a temperature between about 0xc2x0C. to about 20xc2x0 C., preferably about 10xc2x0 C., for a time period between about 0.5 hours to about 2 hours, preferably about 1 hour. Alkylation of the intermediate compound so formed is carried out with the addition of bromoacetic acid. The reaction mixture is then stirred for an additional time period between about 2 hours to about 4 hours, preferably about 3 hours.
In reaction 4 of Scheme 1, the compound of formula II is converted to the corresponding compound of formula I by reacting II with excess acetic anhydride. The reaction mixture so formed is heated to reflux for a time period between about 0.5 hours to about 2 hours, preferably about 1 hour.
In reaction 1 of Scheme 2, the compound of formula VIII, wherein Q is a suitable leaving group, such as halo, preferably fluoro; X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C1-C6)alkyl, hydroxy, trifluoromethyl, (C1-C6)alkoxy, xe2x80x94SOt(C1-C6)alkyl wherein t is zero, one or two, xe2x80x94CO2R8 or xe2x80x94CONR9R10; wherein R8, R9 and R10 are each independently selected from hydrogen, (C1-C4)alkyl, phenyl or naphthyl, wherein said phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, cyano and xe2x80x94SOk(C1-C6)alkyl wherein k is zero, one or two; and R2 is hydrogen, (C1-C4)alkyl, phenyl or naphthyl, wherein said phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, cyano and xe2x80x94SOk(C1-C6)alkyl wherein k is zero, one or two; is converted to the corresponding compound of formula VII, wherein R1 is a group of the formula G1, G2, G3, G4, G5 or G6 depicted below, 
a is zero to four; p is 1, 2 or 3; R4 is selected from the group consisting of hydrogen, (C1-C6)alkyl optionally substituted with (C1-C6)alkoxy or one to three fluorine atoms, or [(C1-C4)alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH2)qxe2x80x94, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and q is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, cyano and xe2x80x94SOg(C1-C6)alkyl, wherein g is zero, one or two; R5 is selected from the group consisting of hydrogen, (C1-C6)alkyl, [(C1-C4)alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH2)rxe2x80x94, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and r is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6)alkyl, cyano and xe2x80x94SOj(C1-C6)alkyl, wherein j is zero, one or two; or R4 and R5 taken together form a 2 to 4 carbon chain; R6 is hydrogen or (C1-C6)alkyl; each R7 is, independently, (C1-C4)alkyl or a (C1-C4)methylene bridge from one of the ring carbons of the piperazine ring of G1 to the same or another ring carbon or a ring nitrogen of the piperazine ring of G1 having an available bonding site, or to a carbon of R4 having an available bonding site; and E, of formula G3, is oxygen, sulfur, SO or SO2; by reacting VIII with a compound of formula R1H, wherein H refers to a hydrogen atom on group E from G3 or nitrogen atoms from G1, G2, G4, G5 or G6 and R1 is defined as above, in the presence of base. This reaction is generally carried out at a temperature from about 25xc2x0 C. to about 140xc2x0 C., preferably at about the reflux temperature, in a polar aprotic solvent, such as dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone, preferably N-methyl-2-pyrrolidinone. Suitable bases include anhydrous sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, as well as amines such as pyrrolidine, triethylamine and pyridine. Anhydrous potassium carbonate is preferred.
In reaction 2 of Scheme 2, the compound of formula VII is converted to the corresponding compound of formula VI by subjecting VII to an Aldol condensation-elimination. In an Aldol condensation, the compound of the formula VII is reacted with a compound of the formula I 
in the presence of a base, to form an Aldol intermediate of the formula IX 
which may be isolated or, preferably, converted directly in the same reaction step to a compound of formula VI by the loss of water. The degree of completion for the conversion of compound of formula IX to the aldol product of formula VI may be assessed using one or more analytical techniques, such as thin layer chromatography (tlc) or high pressure liquid chromatography (hplc). In some instances it may be possible or desirable to isolate the intermediate of formula IX. In such case, the compound of formula IX may be converted into the compound of formula VI by the elimination of water using techniques which are familiar to those skilled in the art, for example, by heating to the reflux temperature a solution of the compound of formula IX in a solvent such as benzene, toluene or xylene, in the presence of a catalytic amount of benzene- or p-toluene-sulfonic acid with provision for the removal of the water generated. Such water removal techniques may involve the use of molecular sieves or a Dean-Stark trap to isolate the water created as an azeotrope with the solvent.
The Aldol reaction is typically carried out in an ether solvent such as methyl t-butyl ether, isopropyl ether or tetrahydrofuran, at a temperature from about xe2x88x9278xc2x0 C. to about 25xc2x0 C. Preferably, this reaction is carried out in tetrahydrofuran at about 25xc2x0 C. Suitable bases for use in the aldol formation step include sodium hydride, potassium-tert-butoxide, lithium diisopropylamide, sodium bis(trimethylsilyl)amide and lithium bis(trimethylsilyl)amide. Sodium bis(trimethylsilyl)amide is preferred. Aldol condensations are described in xe2x80x9cModern Synthetic Reactions,xe2x80x9d Herbert O. House, 2d. Edition, W. A. Benjamin, Menlo Park, Calif., 629-682 (1972) and Tetrahedron, 38 (20), 3059 (1982).
The compounds of formula VI which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of formula VI from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of formula VI are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
The compounds of formula VI and their pharmaceutically acceptable salts (hereinafter also referred to as xe2x80x9cthe active compoundxe2x80x9d) are useful psychotherapeutics and are potent agonists and/or antagonists of the serotonin 1A (5-HT1A) and/or serotonin 1D (5-HT1D) receptors. The active compound is useful in the treatment of hypertension, depression, generalized anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction (e.g., premature ejaculation), eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., addictions to alcohol, cocaine, heroin, phenolbarbitol, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer""s disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson""s diseases (e.g., dementia in Parkinson""s disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, Fibromyalgia Syndrome, stress incontinence, Tourette syndrome, trichotillomania, kleptomania, male impotence, cancer (e.g. small cell lung carcinoma), chronic paroxysmal hemicrania and headache (associated with vascular disorders).
The affinities of the compounds of formula VI for the various serotonin-1 receptors can be determined using standard radioligand binding assays as described in the literature. The 5-HT1A affinity can be measured using the procedure of Hoyer et al. (Brain Res., 376, 85 (1986)). The 5-HT1D affinity can be measured using the procedure of Heuring and Peroutka (J. Neurosci., 7, 894 (1987)).
The in vitro activity of the compounds of formula VI at the 5-HT1D binding site may be determined according to the following procedure. Bovine caudate tissue is homogenized and suspended in 20 volumes of a buffer containing 50 mM TRIS.hydrochloride (tris[hydroxymethyl]aminomethane hydrochloride) at a pH of 7.7. The homogenate is then centrifuged at 45,000 G for 10 minutes. The supernatant is then discarded and the resulting pellet resuspended in approximately 20 volumes of 50 mM TRIS.hydrochloride buffer at pH 7.7. This suspension is then pre-incubated for 15 minutes at 37xc2x0 C., after which the suspension is centrifuged again at 45,000 G for 10 minutes and the supernatant discarded. The resulting pellet (approximately 1 gram) is resuspended in 150 ml of a buffer of 15 mM TRIS.hydrochloride containing 0.01 percent ascorbic acid with a final pH of 7.7 and also containing 10 xcexcM pargyline and 4 mM calcium chloride (CaCl2). The suspension is kept on ice at least 30 minutes prior to use.
The inhibitor, control or vehicle is then incubated according to the following procedure. To 50 xcexcl of a 20 percent dimethylsulfoxide (DMSO)/80 percent distilled water solution is added 200 xcexcl of tritiated 5-hydroxytryptamine (2 nM) in a buffer of 50 mM TRIS.hydrochloride containing 0.01 percent ascorbic acid at pH 7.7 and also containing 10 xcexcM pargyline and 4 xcexcM calcium chloride, plus 100 nM of 8-hydroxy-DPAT (dipropylaminotetraline) and 100 nM of mesulergine. To this mixture is added 750 xcexcl of bovine caudate tissue, and the resulting suspension is vortexed to ensure a homogenous suspension. The suspension is then incubated in a shaking water bath for 30 minutes at 25xc2x0 C. After incubation is complete, the suspension is filtered using glass fiber filters (e.g., Whatman GFB-filters(trademark)). The pellet is then washed three times with 4 ml of a buffer of 50 mM TRIS.hydrochloride at pH 7.7. The pellet is then placed in a scintillation vial with 5 ml of scintillation fluid (aquasol 2(trademark)) and allowed to sit overnight. The percent inhibition can be calculated for each dose of the compound. An IC50 value can then be calculated from the percent inhibition values.
The activity of compounds of formula VI for 5-HT1A binding ability can be determined according to the following procedure Rat brain cortex tissue is homogenized and divided into samples of 1 gram lots and diluted with 10 volumes of 0.32 M sucrose solution. The suspension is then centrifuged at 900 G for 10 minutes and the supernate separated and recentrifuged at 70,000 G for 15 minutes. The supernate is discarded and the pellet resuspended in 10 volumes of 15 mM TRIS.hydrochloride at pH 7.5. The suspension is allowed to incubate for 15 minutes at 37xc2x0 C. After pre-incubation is complete, the suspension is centrifuged at 70,000 G for 15 minutes and the supernate discarded. The resulting tissue pellet is resuspended in a buffer of 50 mM TRIS.hydrochloride at pH 7.7 containing 4 mM of calcium chloride and 0.01 percent ascorbic acid. The tissue is stored at xe2x88x9270xc2x0 C. until ready for an experiment. The tissue can be thawed immediately prior to use, diluted with 10 xcexcm pargyline and kept on ice.
The tissue is then incubated according to the following procedure. Fifty microliters of control, inhibitor, or vehicle (1 percent DMSO final concentration) is prepared at various dosages. To this solution is added 200 xcexcl of tritiated DPAT at a concentration of 1.5 nM in a buffer of 50 mM TRIS.hydrochloride at pH 7.7 containing 4 mM calcium chloride, 0.01 percent ascorbic acid and pargyline. To this solution is then added 750 xcexcl of tissue and the resulting suspension is vortexed to ensure homogeneity. The suspension is then incubated in a shaking water bath for 30 minutes at 37xc2x0 C. The solution is then filtered, washed twice with 4 ml of 10 mM TRIS.hydrochloride at pH 7.5 containing 154 mM of sodium chloride. The percent inhibition is calculated for each dose of the compound, control or vehicle. IC50 values are calculated from the percent inhibition values.
The agonist and antagonist activities of compounds of formula VI at 5-HT1A and 5-HT1D receptors can be determined using a single saturating concentration according to the following procedure. Male Hartley guinea pigs are decapitated and 5-HT1A receptors are dissected out of the hippocampus, while 5-HT1D receptors are obtained by slicing at 350 mM on a Mcllwain tissue chopper and dissecting out the substantia nigra from the appropriate slices. The individual tissues are homogenized in 5 mM HEPES buffer containing 1 mM EGTA (pH 7.5) using a hand-held glass-Teflon(copyright) homogenizer and centrifuged at 35,000xc3x97g for 10 minutes at 4xc2x0 C. The pellets are resuspended in 100 mM HEPES buffer containing 1 mM EGTA (pH 7.5) to a final protein concentration of 20 mg (hippocampus) or 5 mg (substantia nigra) of protein per tube. The following agents are added so that the reaction mix in each tube contained 2.0 mM MgCl2, 0.5 mM ATP, 1.0 mM cAMP, 0.5 mM IBMX, 10 mM phosphocreatine, 0.31 mg/mL creatine phosphokinase, 100 xcexcM GTP and 0.5-1 microcuries of [32P]-ATP (30 Ci/mmol: NEG-003xe2x80x94New England Nuclear). Incubation is initiated by the addition of tissue to siliconized microfuge tubes (in triplicate) at 30xc2x0 C. for 15 minutes. Each tube receives 20 xcexcL tissue, 10 xcexcL drug or buffer (at 10xc3x97 final concentration), 10 xcexcL 32 nM agonist or buffer (at 10xc3x97 final concentration), 20 xcexcL forskolin (3 xcexcM final concentration) and 40 xcexcL of the preceding reaction mix. Incubation is terminated by the addition of 100 xcexcL 2% SDS, 1.3 mM cAMP, 45 mM ATP solution containing 40,000 dpm [3H]-cAMP (30 Ci/mmol: NET-275xe2x80x94New England Nuclear) to monitor the recovery of cAMP from the columns. The separation of [32P]-ATP and [32P]-cAMP is accomplished using the method of Salomon et al., Analytical Biochemistry, 1974, 58, 541-548. Radioactivity is quantified by liquid scintillation counting. Maximal inhibition is defined by 10 xcexcM (R)-8-OH-DPAT for 5-HT1A receptors, and 320 nM 5-HT for 5-HT1D receptors. Percent inhibitions by the test compounds are then calculated in relation to the inhibitory effect of (R)-8-OH-DPAT for 5-HT1A receptors or 5-HT for 5-HT1D receptors. The reversal of agonist induced inhibition of forskolin-stimulated adenylate cyclase activity is calculated in relation to the 32 nM agonist effect.
The compounds of formula VI can be tested for in vivo activity for antagonism of 5-HT1D agonist-induced hypothermia in guinea pigs according to the following procedure.
Male Hartley guinea pigs from Charles River, weighing 250-275 grams on arrival and 300-600 grams at testing, serve as subjects in the experiment. The guinea pigs are housed under standard laboratory conditions on a 7 a.m. to 7 p.m. lighting schedule for at least seven days prior to experimentation. Food and water are available ad libitum until the time of testing.
The compounds of formula VI can be administered as solution in a volume of 1 ml/kg. The vehicle used is varied depending on compound solubility. Test compounds are typically administered either sixty minutes orally (p.o.) or 0 minutes subcutaneously (s.c.) prior to a 5-HT1D agonist, such as [3-(1-methylpyrrolidin-2-ylmethyl)-1H-indol-5-yl]-(3-nitropyridin-3-yl)-amine, which can be prepared as described in PCT publication WO 93/11106, published Jun. 10, 1993, which is administered at a dose of 5.6 mg/kg, s.c. Before a first temperature reading is taken, each guinea pig is placed in a clear plastic shoe box containing wood chips and a metal grid floor and allowed to acclimate to the surroundings for 30 minutes. Animals are then returned to the same shoe box after each temperature reading. Prior to each temperature measurement each animal is firmly held with one hand for a 30-second period. A digital thermometer with a small animal probe is used for temperature measurements. The probe is made of semi-flexible nylon with an epoxy tip. The temperature probe is inserted 6 cm into the rectum and held there for 30 seconds or until a stable recording is obtained. Temperatures are then recorded.
In p.o. screening experiments, a xe2x80x9cpre-drugxe2x80x9d baseline temperature reading is made at xe2x88x9290 minutes, the test compound is given at xe2x88x9260 minutes and an additional xe2x88x9230 minute reading is taken. The 5-HT1D agonist is then administered at 0 minutes and temperatures are taken 30, 60, 120 and 240 minutes later.
In subcutaneous screening experiments, a pre-drug baseline temperature reading is made at xe2x88x9230 minutes. The test compound and 5-HT1D agonists are given concurrently and temperatures are taken at 30, 60, 120 and 240 minutes later.
Data are analyzed with two-way analysis of variants with repeated measures in Newman-Keuls post hoc analysis.
The active compounds of formula VI can be evaluated as anti-migraine agents by testing the extent to which they mimic sumatriptan in contracting the dog isolated saphenous vein strip [P. P. A. Humphrey et al., Br. J. Pharmacol., 94, 1128 (1988)]. This effect can be blocked by methiothepin, a known serotonin antagonist. Sumatriptan is known to be useful in the treatment of migraine and produces a selective increase in carotid vascular resistance in the anesthetized dog. The pharmacological basis of sumatriptan efficacy has been discussed in W. Fenwick et al., Br. J. Pharmacol., 96, 83 (1989).
The serotonin 5-HT1 agonist activity can be determined by the in vitro receptor binding assays, as described for the 5-HT1A receptor using rat cortex as the receptor source and [3H]-8-OH-DPAT as the radioligand [D. Hoyer et al. Eur. J. Pharm., 118, 13 (1985)] and as described for the 5-HT1D receptor using bovine caudate as the receptor source and [3H]serotonin as the radioligand [R. E. Heuring and S. J. Peroutka, J. Neuroscience, 7, 894 (1987)].
The compounds of formula VI may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents such as tricyclic antidepressants (e.g., amitriptyline, dothiepin, doxepin, trimipramine, butripyline, clomipramine, desipramine, imipramine, iprindole, lofepramine, nortriptyline or protriptyline), monoamine oxidase inhibitors (e.g., isocarboxazid, pheneizine or tranylcyclopramine) or 5-HT re-uptake inhibitors (e.g., fluvoxamine, sertraline, fluoxetine or paroxetine), and/or with antiparkinsonian agents such as dopaminergic antiparkinsonian agents (e.g., levodopa, preferably in combination with a peripheral decarboxylase inhibitor e.g., benserazide or carbidopa, or with a dopamine agonist e.g., bromocriptine, lysuride or pergolide).
The compounds of formula VI and the pharmaceutically acceptable salts thereof, in combination with a 5-HT re-uptake inhibitor (e.g., fluvoxamine, sertraline, fluoxetine or paroxetine), preferably sertraline, or a pharmaceutically acceptable salt or polymorph thereof (the combination of a compound of formula VI with a 5-HT re-uptake inhibitor is referred to herein as xe2x80x9cthe active combinationxe2x80x9d), are useful psychotherapeutics and may be used in the treatment or prevention of disorders the treatment or prevention of which is facilitated by enhanced serotonergic neurotransmission (e.g., hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzheimer""s disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorders, and age-associated memory impairment), Parkinson""s diseases (e.g., dementia in Parkinson""s disease, neuroleptic-induced Parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion) chronic paroxysmal hemicrania and headache (associated with vascular disorders).
Serotonin (5-HT) re-uptake inhibitors, preferably sertraline, exhibit positive activity against depression; chemical dependencies; anxiety disorders including panic disorder, generalized anxiety disorder, agoraphobia, simple phobias, social phobia, and post-traumatic stress disorder; obsessive-compulsive disorder; avoidant personality disorder and premature ejaculation in mammals, including humans, due in part to their ability to block the synaptosomal uptake of serotonin.
U.S. Pat. No. 4,536,518 describes the synthesis, pharmaceutical composition and use of sertraline for depression and is hereby incorporated by reference in its entirety. PCT publication WO 98/14433 relates to novel aralkyl and aralkylidene heterocyclic lactams and imides, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use and is hereby incorporated by reference in its entirety.
Activity of the active combination as antidepressants and related pharmacological properties can be determined by methods (1)-(4) below, which are described in Koe, B. et al., Journal of Pharmacology and Experimental Therapeutics, 226 (3), 686-700 (1983). Specifically, activity can be determined by studying (1) their ability to affect the efforts of mice to escape from a swim-tank (Porsolt mouse xe2x80x9cbehavior despairxe2x80x9d test), (2) their ability to potentiate 5-hydroxytryptophan-induced behavioral symptoms in mice in vivo, (3) their ability to antagonize the serotonin-depleting activity of p-chloroamphetamine hydrochloride in rat brain in vivo, and (4) their ability to block the uptake of serotonin, norepinephrine and dopamine by synaptosomal rat brain cells in vitro. The ability of the active combination to counteract reserpine hypothermia in mice in vivo can be determined according to the methods described in U.S. Pat. No. 4,029,731.
The compositions of the compounds of formula VI may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of formula VI may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcytalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner.
The active compounds of formula VI may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
The active compounds of formula VI may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the active compounds of formula VI are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of formula VI and a suitable powder base such as lactose or starch.
A proposed dose of the active compound of formula VI for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above (e.g., depression) is 0.1 to 200 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
Aerosol formulations for treatment of the conditions referred to above (e.g., migraine) in the average adult human are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d of aerosol contains 20 xcexcg to 1000 xcexcg of the compound of formula VI. The overall daily dose with an aerosol will be within the range 100 xcexcg to 10 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.
In connection with the use of an active compound of formula VI with a 5-HT re-uptake inhibitor, preferably sertraline, for the treatment of subjects possessing any of the above conditions, it is to be noted that these compounds may be administered either alone or in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages. More particularly, the active combination can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, such oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes. In general, the compounds of formula I are present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage and a 5-HT re-uptake inhibitor, preferably sertraline, is present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.
A proposed daily dose of an active compound of formula VI in the combination formulation (a formulation containing an active compound of formula VI and a 5-HT re-uptake inhibitor) for oral, parenteral, rectal or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I per unit dose which could be administered, for example, 1 to 4 times per day.
A proposed daily dose of a 5-HT re-uptake inhibitor, preferably sertraline, in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.1 mg to about 2000 mg, preferably from about 1 mg to about 200 mg of the 5-HT re-uptake inhibitor per unit dose which could be administered, for example, 1 to 4 times per day.
A preferred dose ratio of sertraline to an active compound of formula VI in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.00005 to about 20,000, preferably from about 0,25 to about 2,000.
Aerosol combination formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d of aerosol contains from about 0.01 xcexcg to about 100 mg of the active compound of formula VI, preferably from about 1 xcexcg to about 10 mg of such compound. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.
Aerosol formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d of aerosol contains from about 0.01 mg to about 2000 mg of a 5-HT re-uptake inhibitor, preferably sertraline, preferably from about 1 mg to about 200 mg of sertraline. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.
As previously indicated, a 5-HT reuptake inhibitor, preferably sertraline, in combination with compounds of formula VI are readily adapted to therapeutic use as antidepressant agents. In general, these antidepressant compositions containing a 5-HT re-uptake inhibitor, preferably sertraline, and a compound of formula VI are normally administered in dosages ranging from about 0.01 mg to about 100 mg per kg of body weight per day of a 5-HT re-uptake inhibitor, preferably sertraline, preferably from about 0.1 mg to about 10 mg per kg of body weight per day of sertraline; with from about 0.001 mg to about 100 mg per kg of body weight per day of a compound of formula VI, preferably from about 0.01 mg to about 10 mg per kg of body weight per day of a compound of formula VI, although variations will necessarily occur depending upon the conditions of the subject being treated and the particular route of administration chosen.